Gastrodia elata Blume (GEB), a herbaceous plant from the Orchidaceae family, is the core ingredient of the classic traditional Chinese medicine formula Tianma Gouteng Yin. Its dried tubers have been used in medicine since ancient times, with records dating back to the "Shennong Bencao Jing," and are commonly employed in the treatment of limb numbness and convulsions, boasting a medicinal history of over 1,800 years. However, no studies have yet focused on the changes in differential metabolites in the striatum after GEB treatment.This study aimed to evaluate the protective effects of GEB on MPTP-induced Parkinson's disease (PD) in mice and to explore its potential mechanisms.Mice were randomly divided into a control group, a model group, and GEB treatment groups (100, 200, and 300 mg/kg). After 14 days of GEB pretreatment, a sub-acute PD model was induced by intraperitoneal injection of MPTP (30 mg/kg) once daily for 7 consecutive days. The potential of GEB to improve motor behavior in PD mice was evaluated using gait analysis (GA) and the pole test. Enzyme-linked immunosorbent assay was used to measure interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels in the striatum of PD mice. The effects of GEB on substantia nigra damage were assessed by hematoxylin and eosin staining (HE) and immunohistochemistry. Lastly, the therapeutic effects and potential mechanisms of GEB on MPTP-induced PD mice through striatal metabolomics analysis were investigated.A total of 402 compounds were identified in the GEB ethanol extract, with gastrodin, parishins A, B, C, and E, and 4-hydroxybenzyl alcohol being the major components. These were quantified by HPLC at 2.47%, 2.04%, 1.25%, 0.33%, 1.14%, and 2.88%, respectively. GEB improved the propulsive index and duty cycle of the gait index, reduced climbing time, and inhibited the elevation of inflammatory factors such as IL-1β, IL-6, and TNF-α in the striatum. GEB ameliorated neurodegeneration in the substantia nigra pars compacta and alleviated motor impairments in PD model mice. Furthermore, striatal metabolomics analysis showed that GEB treatment improved various metabolic pathways, including glycerophospholipid, sphingolipid, tyrosine, arachidonic acid, and arginine and proline.GEB extract demonstrated positive ameliorative effects on PD by inhibiting inflammatory responses, ameliorating neuronal damage, and modulating lipid metabolic pathways, and possibly being an ideal candidate for the development of functional foods for PD.Copyright © 2025. Published by Elsevier B.V.